PT - JOURNAL ARTICLE AU - Anna Torrent AU - David Moreno-Delgado AU - Jordi Gómez-Ramírez AU - Daniel Rodríguez-Agudo AU - Carlos Rodríguez-Caso AU - Francisca Sánchez-Jiménez AU - Isaac Blanco AU - Jordí Ortiz TI - H<sub>3</sub> Autoreceptors Modulate Histamine Synthesis through Calcium/Calmodulin- and cAMP-Dependent Protein Kinase Pathways AID - 10.1124/mol.104.005652 DP - 2005 Jan 01 TA - Molecular Pharmacology PG - 195--203 VI - 67 IP - 1 4099 - http://molpharm.aspetjournals.org/content/67/1/195.short 4100 - http://molpharm.aspetjournals.org/content/67/1/195.full SO - Mol Pharmacol2005 Jan 01; 67 AB - H3 autoreceptors provide feedback control of neurotransmitter synthesis in histaminergic neurons, but the transduction pathways involved are poorly understood. In rat brain cortical slices, histamine synthesis can be stimulated by depolarization and inhibited by H3 agonists. We show that histamine synthesis stimulation by depolarization with 30 mM K+ requires extracellular calcium entry, mostly through N-type channels, and subsequent activation of calcium/calmodulin-dependent protein kinase type II. In vitro, this kinase phosphorylated and activated histidine decarboxylase, the histamine-synthesizing enzyme. Inhibition of depolarization-stimulated histamine synthesis by the histamine H3 receptor agonist imetit was impaired by preincubation with pertussis toxin and by the presence of a myristoylated peptide (myristoyl-N-QEHAQEPERQYMHIGTMVE-FAYALVGK) blocking the actions of G-protein βγ subunits. The stimulation of another Gi/o-coupled receptor, adenosine A1, also decreased depolarization-stimulated histamine synthesis. In contrast, protein kinase A activation, which is also repressed by H3 receptors, elicited a depolarization- and calcium/calmodulin-independent stimulation of histamine synthesis. Protein kinase A was able also to phosphorylate and activate histidine decarboxylase in vitro. These results show how depolarization activates histamine synthesis in nerve endings and demonstrate that both pathways modulating neurotransmitter synthesis are controlled by H3 autoreceptors.